Progress in construction of hypoxia-sensitive CAR-T cell for solid tumor therapy

doi:10.19401/j.cnki.1007-3639.2023.01.008

Abstract

Abstract:

Chimeric antigen receptor T (CAR-T) cell therapy, as a kind of tumor immunotherapy, has made remarkable achievements for the treatment of hematological malignancy. Disappointingly, regarding solid tumors, CAR-T cells generally target tumor-associated antigens that are also widely expressed in normal tissues because of the lack of tumor specific antigen, resulting in on-target off-tumor effects, which may even endanger patients’ lives. Measures should be taken to overcome the off-target effects which severely limit the application of CAR-T cell therapy in solid tumors. A feasible strategy is to design hypoxia-sensitive CAR-T cells, which express CAR only in the hypoxic tumor microenvironment. Therefore, the redundant “accidental injury” can be avoided. In this review, common approaches as well as recent advances in the construction of hypoxia-sensitive CAR-T cells were discussed and summarized, which has guiding significance for enhancing the safety of CAR-T cell therapy and promoting the application of CAR-T cell in solid tumors.

Key words: Chimeric antigen receptor T cell therapy, Hypoxia-sensitive, Tumor microenvironment, Solid tumor

CLC Number:

R730.5

XUE Ying, MAO Yunyu, XU Jianqing. Progress in construction of hypoxia-sensitive CAR-T cell for solid tumor therapy[J]. China Oncology, 2023, 33(1): 71-77.

Figures/Tables 1

References 46

[1]	ALLEMANI C, MATSUDA T, DI CARLO V, et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries[J]. Lancet, 2018, 391(10125): 1023-1075. doi: 10.1016/S0140-6736(17)33326-3
[2]	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. doi: 10.3322/caac.21660
[3]	HAN X L, BRYSON P D, ZHAO Y F, et al. Masked chimeric antigen receptor for tumor-specific activation[J]. Mol Ther, 2017, 25(1): 274-284. doi: S1525-0016(16)45366-9 pmid: 28129121
[4]	赵玲娣, 高全立. CAR-T细胞在肿瘤治疗中的研究进展[J]. 中国肿瘤临床, 2015, 42(3): 190-194.
	ZHAO L D, GAO Q L. Research progress of CAR T-cell in tumor therapy[J]. Chin J Clin Oncol, 2015, 42(3): 190-194.
[5]	荣斌, 吴纯启, 原野, 等. CAR-T细胞治疗产品及其非临床评价研究概述[J]. 中南药学, 2019, 17(9): 1381-1385.
	RONG B, WU C Q, YUAN Y, et al. Non-clinical evaluation of CAR-T cell therapy products[J]. Central South Pharm, 2019, 17(9): 1381-1385.
[6]	SHKLOVSKAYA E, RIZOS H. MHC class Ⅰ deficiency in solid tumors and therapeutic strategies to overcome it[J]. Int J Mol Sci, 2021, 22(13): 6741. doi: 10.3390/ijms22136741
[7]	GARRIDO F, APTSIAURI N. Cancer immune escape: MHC expression in primary tumours versus metastases[J]. Immunology, 2019, 158(4): 255-266. doi: 10.1111/imm.13114 pmid: 31509607
[8]	常征, 陈学武, 王丽, 等. 嵌合抗原受体T细胞治疗恶性肿瘤的研究进展[J]. 药学研究, 2015, 34(9): 534-536.
	CHANG Z, CHEN X W, WANG L, et al. Research progress of chimeric antigen receptor modified T cells in malignant tumor[J]. J Pharm Res, 2015, 34(9): 534-536.
[9]	LIM W A, JUNE C H. The principles of engineering immune cells to treat cancer[J]. Cell, 2017, 168(4): 724-740. doi: S0092-8674(17)30064-8 pmid: 28187291
[10]	JUNE C H, O’CONNOR R S, KAWALEKAR O U, et al. CAR-T cell immunotherapy for human cancer[J]. Science, 2018, 359(6382): 1361-1365. doi: 10.1126/science.aar6711
[11]	ZOU F, TAN J Z, LIU T, et al. The CD39 + HBV surface protein-targeted CAR-T and personalized tumor-reactive CD8 + T cells exhibit potent anti-HCC activity[J]. Mol Ther, 2021, 29(5): 1794-1807. doi: 10.1016/j.ymthe.2021.01.021
[12]	TANG X J, ZHOU Y, LI W J, et al. T cells expressing a LMP1-specific chimeric antigen receptor mediate antitumor effects against LMP1-positive nasopharyngeal carcinoma cells in vitro and in vivo[J]. J Biomed Res, 2014, 28(6): 468-475. doi: 10.7555/JBR.28.20140066 pmid: 25469116
[13]	彭灿灿, 王惠明. CAR-T细胞治疗实体瘤的脱靶效应及优化方略[J]. 中国免疫学杂志, 2021, 37(22): 2754-2758.
	PENG C C, WANG H M. Off-target effect and optimization of CAR-T cell therapy in solid tumors[J]. Chin J Immunol, 2021, 37(22): 2754-2758.
[14]	SCHUBERT M L, SCHMITT M, WANG L, et al. Side-effect management of chimeric antigen receptor (CAR) T-cell therapy[J]. Ann Oncol, 2021, 32(1): 34-48. doi: 10.1016/j.annonc.2020.10.478 pmid: 33098993
[15]	WANG Z G, WU Z Q, LIU Y, et al. New development in CAR-T cell therapy[J]. J Hematol Oncol, 2017, 10(1): 53. doi: 10.1186/s13045-017-0423-1
[16]	QI C S, GONG J F, LI J, et al. Claudin18.2-specific CAR-T cells in gastrointestinal cancers: phase 1 trial interim results[J]. Nat Med, 2022, 28(6): 1189-1198. doi: 10.1038/s41591-022-01800-8
[17]	TCHOU J, ZHAO Y B, LEVINE B L, et al. Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer[J]. Cancer Immunol Res, 2017, 5(12): 1152-1161. doi: 10.1158/2326-6066.CIR-17-0189 pmid: 29109077
[18]	XIAO Y, YU D H. Tumor microenvironment as a therapeutic target in cancer[J]. Pharmacol Ther, 2021, 221: 107753. doi: 10.1016/j.pharmthera.2020.107753
[19]	LUO X, XU J, YU J H, et al. Shaping immune responses in the tumor microenvironment of ovarian cancer[J]. Front Immunol, 2021, 12: 692360. doi: 10.3389/fimmu.2021.692360
[20]	SATILMIS B, SAHIN T T, CICEK E, et al. Hepatocellular carcinoma tumor microenvironment and its implications in terms of anti-tumor immunity: future perspectives for new therapeutics[J]. J Gastrointest Canc, 2021, 52(4): 1198-1205. doi: 10.1007/s12029-021-00725-8
[21]	KUMARI S, ADVANI D, SHARMA S, et al. Combinatorial therapy in tumor microenvironment: where do we stand?[J]. Biochim Biophys Acta Rev Cancer, 2021, 1876(2): 188585. doi: 10.1016/j.bbcan.2021.188585
[22]	PLUNDRICH D, CHIKHLADZE S, FICHTNER-FEIGL S, et al. Molecular mechanisms of tumor immunomodulation in the microenvironment of colorectal cancer[J]. Int J Mol Sci, 2022, 23(5): 2782. doi: 10.3390/ijms23052782
[23]	SIMSEK H, KLOTZSCH E. The solid tumor microenvironment-Breaking the barrier for T cells[J]. BioEssays, 2022, 44(6): 2100285. doi: 10.1002/bies.202100285
[24]	GOLIWAS K F, DESHANE J S, ELMETS C A, et al. Moving immune therapy forward targeting TME[J]. Physiol Rev, 2021, 101(2): 417-425. doi: 10.1152/physrev.00008.2020
[25]	LI Y, ZHAO L, LI X F. Hypoxia and the tumor microenvironment[J]. Technol Cancer Res Treat, 2021, 20: 15330338211036304.
[26]	SINGH S R, RAMESHWAR P, SIEGEL P. Targeting tumor microenvironment in cancer therapy[J]. Cancer Lett, 2016, 380(1): 203-204. doi: 10.1016/j.canlet.2016.04.009 pmid: 27060765
[27]	BERAHOVICH R, LIU X H, ZHOU H, et al. Hypoxia selectively impairs CAR-T cells in vitro[J]. Cancers (Basel), 2019, 11(5): 602. doi: 10.3390/cancers11050602
[28]	SCHILIRO C, FIRESTEIN B L. Mechanisms of metabolic reprogramming in cancer cells supporting enhanced growth and proliferation[J]. Cells, 2021, 10(5): 1056. doi: 10.3390/cells10051056
[29]	VAUPEL P, MULTHOFF G. Revisiting the Warburg effect: historical dogma versus current understanding[J]. J Physiol, 2021, 599(6): 1745-1757. doi: 10.1113/JP278810
[30]	WANG B, ZHAO Q, ZHANG Y Y, et al. Targeting hypoxia in the tumor microenvironment: a potential strategy to improve cancer immunotherapy[J]. J Exp Clin Cancer Res, 2021, 40(1): 24. doi: 10.1186/s13046-020-01820-7
[31]	ALBADARI N, DENG S S, LI W. The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy[J]. Expert Opin Drug Discov, 2019, 14(7): 667-682. doi: 10.1080/17460441.2019.1613370
[32]	AL TAMEEMI W, DALE T P, AL-JUMAILY R M K, et al. Hypoxia-modified cancer cell metabolism[J]. Front Cell Dev Biol, 2019, 7: 4. doi: 10.3389/fcell.2019.00004 pmid: 30761299
[33]	FALLAH J, RINI B I. HIF inhibitors: status of current clinical development[J]. Curr Oncol Rep, 2019, 21(1): 6. doi: 10.1007/s11912-019-0752-z pmid: 30671662
[34]	COWMAN S J, KOH M Y. Revisiting the HIF switch in the tumor and its immune microenvironment[J]. Trends Cancer, 2022, 8(1): 28-42. doi: 10.1016/j.trecan.2021.10.004
[35]	LEE J W, BAE S H, JEONG J W, et al.Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions[J]. Exp Mol Med, 2004, 36(1): 1-12. doi: 10.1038/emm.2004.1
[36]	朱秀秀, 王玲, 沈俊杰, 等. 靶向PSCA的缺氧诱导型CAR-T的构建及体外效能研究[J]. 中国细胞生物学学报, 2019, 41(4): 636-644.
	ZHU X X, WANG L, SHEN J J, et al. Construction and in vitro potency investigation of hypoxia-inducible CAR-T targeting PSCA[J]. Chin J Cell Biol, 2019, 41(4): 636-644.
[37]	LEE J W, KO J, JU C, et al. Hypoxia signaling in human diseases and therapeutic targets[J]. Exp Mol Med, 2019, 51(6): 1-13. doi: 10.1038/s12276-019-0235-1 pmid: 31221962
[38]	VITO A, EL-SAYES N, MOSSMAN K. Hypoxia-driven immune escape in the tumor microenvironment[J]. Cells, 2020, 9(4): 992. doi: 10.3390/cells9040992
[39]	KE Q D, COSTA M. Hypoxia-inducible factor-1 (HIF-1)[J]. Mol Pharmacol, 2006, 70(5): 1469-1480. doi: 10.1124/mol.106.027029 pmid: 16887934
[40]	CORRADO C, FONTANA S. Hypoxia and HIF signaling: one axis with divergent effects[J]. Int J Mol Sci, 2020, 21(16): 5611. doi: 10.3390/ijms21165611
[41]	JUILLERAT A, MARECHAL A, FILHOL J M, et al. An oxygen sensitive self-decision making engineered CAR T-cell[J]. Sci Rep, 2017, 7: 39833. doi: 10.1038/srep39833 pmid: 28106050
[42]	LIAO Q B, HE H, MAO Y Y, et al. Engineering T cells with hypoxia-inducible chimeric antigen receptor (HiCAR) for selective tumor killing[J]. Biomark Res, 2020, 8(1): 56. doi: 10.1186/s40364-020-00238-9 pmid: 33292642
[43]	陈文艳, 熊建萍. 肿瘤缺氧及其靶向治疗研究进展[J]. 国际肿瘤学杂志, 2006, 33(1): 8-11.
	CHEN W Y, XIONG J P. Research progress of tumor hypoxia and its targeted therapy[J]. J Int Oncol, 2006, 33(1): 8-11.
[44]	KOSTI P, OPZOOMER J W, LARIOS-MARTINEZ K I, et al. Hypoxia-sensing CAR T cells provide safety and efficacy in treating solid tumors[J]. Cell Rep Med, 2021, 2(4): 100227.
[45]	BRANDT L J B, BARNKOB M B, MICHAELS Y S, et al. Emerging approaches for regulation and control of CAR T cells: a mini review[J]. Front Immunol, 2020, 11: 326. doi: 10.3389/fimmu.2020.00326 pmid: 32194561
[46]	LIIKANEN I, LAUHAN C, QUON S, et al. Hypoxia-inducible factor activity promotes antitumor effector function and tissue residency by CD8 + T cells[J]. J Clin Invest, 2021, 131(7): e143729. doi: 10.1172/JCI143729